Angiogenesis is an important component of the development, growth, and spread of many types of tumors, including malignancies of the skin. VEGF (vascular endothelial growth factor-A) is a potent pro-angiogenic factor, which has been implicated in a variety of processes in the skin, including tumorigenesis. In the skin, high VEGF levels are associated with enhanced papilloma development, increased squamous cell carcinoma numbers, and a higher incidence of lymph node metastasis. In general, VEGF is described as an endothelial cell-specific growth factor and its ability to promote tumorigenesis has been completely linked to its pro-angiogenic effects. However, evidence that the effects of VEGF may not be restricted to endothelial cells is emerging, as VEGF receptors (VEGFR-1 and VEGFR-2) can be expressed by a subset of non-endothelial cell types. Recently, our laboratory has discovered that one of these receptors, VEGFR-1, is expressed by epidermal keratinocytes. We have also demonstrated a functional role for VEGFR-1 in keratinocyte proliferation in vitro and in vivo during the proliferative phase of cutaneous wound healing. Because excessive proliferation is integral to tumor development, our results suggest that VEGF, through interaction with VEGFR- 1, may influence cutaneous tumorigenesis by signaling directly in keratinocytes. The goal of the proposed studies is to determine whether VEGF can directly stimulate keratinocytes through VEGFR-1, and if this direct keratinocyte stimulation by VEGF is involved in skin carcinogenesis. To carry out these studies we will use novel genetically modified mice, which will allow the temporal deletion of VEGFR-1 specifically in keratinocytes. Mouse models of skin carcinogenesis in addition to human skin cancer samples will be used to carry out the following specific aims: 1) Determine the role of keratinocyte VEGFR-1 in chemical skin carcinogenesis, 2) Evaluate the role of keratinocyte VEGFR-1 in photocarcinogenesis, and 3) Examine VEGFR-1 expression and signaling in human keratinocytes and skin tumors. These studies could potentially reveal a novel biological function for VEGF and could uncover a new, direct mechanism for the involvement of VEGF in the promotion of skin carcinogenesis. The data generated from these experiments will provide new information about the mechanisms involved in skin cancer development, which could be important for treating millions of patients diagnosed with this disease each year. PROJECT NARRATIVE: Non-melanoma skin cancer is the most common type of cancer diagnosed, with over a million new cases reported in the U.S. every year. The studies proposed in this application will examine new pathways involved skin cancer development. The information resulting from these studies could lead to a better understanding about the development and growth of skin tumors, and could also result in the development of better ways to prevent and treat skin cancer.